U.S. patent number 6,624,185 [Application Number 10/231,432] was granted by the patent office on 2003-09-23 for diarylcycloalkyl derivatives, processes for their preparation and their use as pharmaceuticals.
This patent grant is currently assigned to Aventis Pharma Deutschland GmbH. Invention is credited to Eugen Falk, Wendelin Frick, Heiner Glombik, Stefanie Keil, Hans-Ludwig Schafer, Lothar Schwink, Wolfgang Wendler.
United States Patent |
6,624,185 |
Glombik , et al. |
September 23, 2003 |
**Please see images for:
( Certificate of Correction ) ** |
Diarylcycloalkyl derivatives, processes for their preparation and
their use as pharmaceuticals
Abstract
Diarylcycloalkyl derivatives and their physiologically
acceptable salts and physiologically functional derivatives are
disclosed. The compounds include those of formula I, ##STR1## in
which the radicals are as defined, and their physiologically
acceptable salts and processes for their preparation. The compounds
typically have lipid- and/or triglyceride-lowering properties and
are suitable, for example, for the treatment of disorders of lipid
metabolism, of type II diabetes, and of syndrome X.
Inventors: |
Glombik; Heiner (Hofheim,
DE), Falk; Eugen (Frankfurt, DE), Frick;
Wendelin (Hunstetten-Beuerbach, DE), Keil;
Stefanie (Hofheim, DE), Schafer; Hans-Ludwig
(Hochheim, DE), Schwink; Lothar (Stadtallendorf,
DE), Wendler; Wolfgang (Idstein, DE) |
Assignee: |
Aventis Pharma Deutschland GmbH
(Frankfurt am Main, DE)
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Family
ID: |
26010044 |
Appl.
No.: |
10/231,432 |
Filed: |
August 30, 2002 |
Foreign Application Priority Data
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Aug 31, 2001 [DE] |
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101 42 734 |
May 24, 2002 [DE] |
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102 23 273 |
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Current U.S.
Class: |
514/374;
548/236 |
Current CPC
Class: |
A61P
9/10 (20180101); C07D 413/12 (20130101); A61P
19/10 (20180101); A61P 1/04 (20180101); A61P
9/04 (20180101); A61P 29/00 (20180101); A61P
3/06 (20180101); A61P 43/00 (20180101); A61P
3/00 (20180101); C07D 263/32 (20130101); A61P
25/28 (20180101); A61P 1/14 (20180101); A61P
3/10 (20180101) |
Current International
Class: |
C07D
413/00 (20060101); C07D 263/00 (20060101); C07D
413/12 (20060101); C07D 263/32 (20060101); A61K
031/421 (); A61P 003/10 (); C07D 236/34 () |
Field of
Search: |
;548/236 ;514/374 |
References Cited
[Referenced By]
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01/91752 |
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Dec 2001 |
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WO |
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Primary Examiner: Ramsuer; Robert W.
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner, L.L.P.
Claims
What is claimed is:
1. A compound of formula I ##STR77##
in which Ring A is (C.sub.3 -C.sub.8)-cycloalkyl or (C.sub.3
-C.sub.8)-cycloalkenyl where, in the cycloalkyl or cycloalkenyl
rings, one or more carbon atoms may be replaced by oxygen atoms;
R1, R2, R4, R5 independently of one another are H, F, Cl, Br, OH,
NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 -C.sub.6)-alkyl or
O-(C.sub.1 -C.sub.6)-alkyl; R3 is H or (C.sub.1 -C.sub.6)-alkyl; X
is (C.sub.1 -C.sub.6)-alkyl where, in the alkyl group, one or more
carbon atoms may be replaced by oxygen atoms; Y is (C.sub.1
-C6)-alkyl where, in the alkyl group, one or more carbon atoms may
be replaced by oxygen atoms;
and its physiologically acceptable salts.
2. The compound of claim 1 and its physiologically acceptable
salts, wherein R5 is (C.sub.1 -C.sub.6)-alkyl.
3. The compound of claim 1 and its physiologically acceptable
salts, wherein Ring A is (C.sub.3 -C.sub.8)-cycloalkyl or (C.sub.3
-C.sub.8)-cycloalkenyl.
4. A compound of formula Ia ##STR78##
wherein Ring A is cyclohexyl; R1, R2 independently of one another
are H,. F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1
-C.sub.6)-alkyl or O-(C.sub.1 -C.sub.6)-alkyl; R3 is H or (C.sub.1
-C.sub.6)-alkyl; X is (C.sub.1 -C.sub.6)-alkyl where, in the alkyl
group, one or more carbon atoms may be replaced by oxygen atoms; Y
is (C.sub.1 -C.sub.6)-alkyl where, in the alkyl group, one or more
carbon atoms may be replaced by oxygen atoms;
and its physiologically acceptable salts.
5. A pharmaceutical, comprising: at least one compound or
physiologically acceptable salt of claim 1; and a pharmaceutically
acceptable carrier.
6. A pharmaceutical, comprising: at least one compound or
physiologically acceptable salt of claim 1; at least one further
active compound; and a pharmaceutically acceptable carrier.
7. A pharmaceutical, comprising: at least one compound or
physiologically acceptable salt of claim 1; at least one lipid- or
triglyceride-lowering active compound; and a pharmaceutically
acceptable carrier.
8. A method of treating a lipid metabolism disorder, comprising:
administering to a host in need of such treatment an effective
amount of at least one compound or physiologically acceptable salt
of claim 1 or claim 4.
9. A method of treating type II diabetes, comprising: administering
to a host in need of such treatment an effective amount of at least
one compound or physiologically acceptable salt of claim 1 or claim
4.
10. A method of treating syndrome X, comprising: administering to a
host in need of such treatment an effective amount of at least one
compound or physiologically acceptable salt of claim 1 or claim
4.
11. A method of treating disturbed glucose tolerance, comprising:
administering to a host in need of such treatment an effective
amount of at least one compound or physiologically acceptable salt
of claim 1 or claim 4.
12. A method of treating eating disorders, comprising:
administering to a host in need of such treatment an effective
amount of at least one compound or physiologically acceptable salt
of claim 1 or claim 4.
13. A method of treating obesity, comprising: administering to a
host in need of such treatment an effective amount of at least one
compound or physiologically acceptable salt of claim 1 or claim
4.
14. A method of treating cardiomyopathy, comprising: administering
to a host in need of such treatment an effective amount of at least
one compound or physiologically acceptable salt of claim 1 or claim
4.
15. A method of treating cardiac insufficiency, comprising:
administering to a host in need of such treatment an effective
amount of at least one compound or physiologically acceptable salt
of claim 1 or claim 4.
16. A method of treating osteoporosis, comprising: administering to
a host in need of such treatment an effective amount of at least
one compound or physiologically acceptable salt of claim 1 or claim
4.
17. A method of treating atherosclerosis, comprising: administering
to a host in need of such treatment an effective amount of at least
one compound or physiologically acceptable salt of claim 1 or claim
4.
18. A method of treating Alzheimer's disease, comprising:
administering to a host in need of such treatment an effective
amount of at least one compound or physiologically acceptable salt
of claim 1 or claim 4.
19. A method of treating inflammation, comprising: administering to
a host in need of such treatment an effective amount of at least
one compound or physiologically acceptable salt of claim 1 or claim
4.
20. The method of treating a lipid metabolism disorder of claim 8,
further comprising administering to a host in need of such
treatment an effective amount of at least one further active
compound.
21. The method of treating type II diabetes of claim 9, further
comprising administering to a host in need of such treatment an
effective amount of at least one further active compound.
22. The method of treating syndrome X of claim 10, further
comprising administering to a host in need of such treatment an
effective amount of at least one further active compound.
23. A process for preparing a pharmaceutical, comprising: mixing at
least one compound or physiologically acceptable salt of claim 1
with a pharmaceutically acceptable carrier to form a mixture; and
bringing this mixture into a form suitable for administration to
form the pharmaceutical.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority under 35 U.S.C. .sctn.119
of German Application Nos. 10142734.4 and 10223273.3, filed Aug.
31, 2001 and May 24, 2002, respectively, the disclosures of which
are expressly incorporated by reference herein.
DESCRIPTION
1. Field of the Invention
The invention relates to diarylcycloalkyl derivatives and to their
physiologically acceptable salts and physiologically functional
derivatives.
2. Background of the Invention
Compounds of similar structure have already been described in the
prior art for the treatment of hyperlipidemia and diabetes
(PCT/US/0011490).
SUMMARY OF THE INVENTION
An object of the invention is to provide compounds having a
therapeutically exploitable triglyceride-lowering action and a
favorable effect on lipid and carbohydrate metabolism, such as for
syndromes of dyslipidemias, type II diabetes and the metabolic
syndrome/syndrome X. Another object of the invention is to provide
compounds having improved action compared with the compounds of
PCT/US00/14490. The compounds of the invention may activate the
PPAR.alpha. receptor.
In one aspect, the present invention is directed to a compound of
formula I ##STR2##
in which Ring A is (C.sub.3 -C8)-cycloalkyl or (C.sub.3
-C.sub.8)-cycloalkenyl where, in the cycloalkyl or cycloalkenyl
rings, one or more carbon atoms may be replaced by oxygen atoms;
R1, R2, R4, R5 independently of one another are H, F, Cl, Br, OH,
NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 -C.sub.6)-alkyl or
O-(C.sub.1 -C.sub.6)-alkyl; R3 is H or (C.sub.1 -C.sub.6)-alkyl; x
is (C.sub.1 -C.sub.6)-alkyl where, in the alkyl group, one or more
carbon atoms may be replaced by oxygen atoms; Y is (C.sub.1
-C.sub.6)-alkyl where, in the alkyl group, one or more carbon atoms
may be replaced by oxygen atoms;
and its physiologically acceptable salts.
In another aspect, the present invention is directed to a compound
of formula Ia ##STR3##
wherein Ring A is cyclohexyl; R1, R2 independently of one another
are H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1
-C.sub.6)-alkyl or O-(C.sub.1 -C.sub.6)-alkyl; R3 is H or (C.sub.1
-C.sub.6)-alkyl; X is (C.sub.1 -C.sub.6)-alkyl where, in the alkyl
group, one or more carbon atoms may be replaced by oxygen atoms; Y
is (C.sub.1 -C.sub.6)-alkyl where, in the alkyl group, one or more
carbon atoms may be replaced by oxygen atoms; and its
physiologically acceptable salts.
In another aspect, the present invention is directed to a
pharmaceutical, comprising at least one of the above compounds or
physiologically acceptable salts and a pharmaceutically acceptable
carrier.
In still another aspect, the present invention is directed to a
pharmaceutical, comprising at least one of the above compounds or
physiologically acceptable salts, at least one further active
compound, and a pharmaceutically acceptable carrier.
In yet another aspect, the present invention is directed to a
pharmaceutical, comprising at least one of the above compounds or
physiologically acceptable salts, at least one lipid- or
triglyceride-lowering active compound, and a pharmaceutically
acceptable carrier.
The present invention is also directed to a method of treating a
lipid metabolism disorder, type II diabetes, syndrome X, disturbed
glucose tolerance, eating disorders, obesity, cardiomyopathy,
cardiac insufficiency, osteoporosis, atherosclerosis, Alzheimer's
disease, or inflammation, comprising administering to a host in
need of such treatment an effective amount of at least one the
above compounds or physiologically acceptable salts.
In another aspect, the present invention is directed to a method of
treating a lipid metabolism disorder, type II diabetes, or syndrome
X, comprising administering to a host in need of such treatment an
effective amount of a combination of at least one of the above
compounds or physiologically acceptable salts and at least one
further active compound.
In another aspect, the present invention is directed to a process
for preparing a pharmaceutical, comprising mixing at least one of
the above compounds or physiologically acceptable salts with a
pharmaceutically acceptable carrier to form a mixture and bringing
this mixture into a form suitable for administration to form the
pharmaceutical.
DESCRIPTION OF THE INVENTION
The particulars shown herein are by way of example and for purposes
of illustrative discussion of the various embodiments of the
present invention only and are presented in the cause of providing
what is believed to be the most useful and readily understood
description of the principles and conceptual aspects of the
invention. In this regard, no attempt is made to show details of
the invention in more detail than is necessary for a fundamental
understanding of the invention, the description making apparent to
those skilled in the art how the several forms of the invention may
be embodied in practice.
Unless otherwise stated, a reference to a compound or component,
includes the compound or component by itself, as well as in
combination with other compounds or components, such as mixtures of
compounds.
The invention relates to compounds of formula I ##STR4##
in which Ring A is (C.sub.3 -C.sub.8)-cycloalkyl or (C.sub.3
-C.sub.8)-cycloalkenyl where, in the cycloalkyl or cycloalkenyl
rings, one or more carbon atoms may be replaced by oxygen atoms;
R1, R2, R4, R5 independently of one another are H, F, Cl, Br, OH,
NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1 -C.sub.6)-alkyl or
O-(C.sub.1 -C.sub.6)-alkyl; R3 is H or (C.sub.1 -C.sub.6)-alkyl; X
is (C.sub.1 -C.sub.6)-alkyl where, in the alkyl group, one or more
carbon atoms may be replaced by oxygen atoms; Y is (C.sub.1
-C.sub.6)-alkyl where, in the alkyl group, one or more carbon atoms
may be replaced by oxygen atoms;
and their physiologically acceptable salts.
The invention also includes compounds of formula I in which Ring A
is (C.sub.3 -C.sub.8)-cycloalkyl or (C.sub.3 -C.sub.8)-cycloalkenyl
where, in the cycloalkyl or cycloalkenyl rings, one or more carbon
atoms may be replaced by oxygen atoms; R1, R2, R4 independently of
one another are H, F, Cl, Br, OH, NO.sub.2, CF3, OCF.sub.3,
(C.sub.1 -C.sub.6)-alkyl or O-(C.sub.1 -C.sub.6)-alkyl; R5 is
(C.sub.1 -C.sub.6)-alkyl; R3 is H or (C.sub.1 -C.sub.6)-alkyl; X is
(C.sub.1 -C.sub.6)-alkyl where, in the alkyl group, one or more
carbon atoms may be replaced by oxygen atoms; Y is (C.sub.1
-C.sub.6)-alkyl where, in the alkyl group, one or more carbon atoms
may be replaced by oxygen atoms;
and their physiologically acceptable salts.
The invention further includes compounds of formula I in which Ring
A is (C.sub.3 -C.sub.8)-cycloalkyl or (C.sub.3
-C.sub.8)-cycloalkenyl; R1, R2 independently of one another are H,
F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1
-C.sub.6)-alkyl or O-(C.sub.1 -C.sub.6)-alkyl; R3 is H or (C.sub.1
-C.sub.6)-alkyl; X is (C.sub.1 -C.sub.6)-alkyl where, in the alkyl
group, one or more carbon atoms may be replaced by oxygen atoms; Y
is (C.sub.1 -C.sub.6)-alkyl where, in the alkyl group, one or more
carbon atoms may be replaced by oxygen atoms;
and their physiologically acceptable salts.
The invention also includes compounds of formula Ia ##STR5##
wherein Ring A is cyclohexyl; R1, R2 independently of one another
are H, F, Cl, Br, OH, NO.sub.2, CF.sub.3, OCF.sub.3, (C.sub.1
-C.sub.6)-alkyl or O-(C.sub.1 -C.sub.6)-alkyl; R3 is H or (C.sub.1
-C.sub.6)-alkyl; X is (C.sub.1 -C.sub.6)-alkyl where, in the alkyl
group, one or more carbon atoms may be replaced by oxygen atoms; Y
is (C.sub.1 -C.sub.6)-alkyl where, in the alkyl group, one or more
carbon atoms may be replaced by oxygen atoms;
and their physiologically acceptable salts.
The invention embraces compounds of formula I in the form of their
racemates, racemic mixtures and pure enantiomers, and also their
diastereomers and mixtures thereof.
The alkyl radicals in the substituents R1, R2, R3, R4 and R5 can be
straight-chain or branched.
Pharmaceutically acceptable salts are suitable for medical
applications because of their greater solubility in water compared
with the starting or base compounds. These salts must have a
pharmaceutically acceptable anion or cation. Suitable
pharmaceutically acceptable acid addition salts of the compounds of
the invention are salts of inorganic acids such as hydrochloric
acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric
acids, and of organic acids such as, for example, acetic acid,
benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric,
gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic,
methanesulfonic, succinic, p-toluenesulfonic and tartaric acids.
Suitable pharmaceutically acceptable basic salts are ammonium
salts, alkali metal salts (such as sodium and potassium salts) and
alkaline earth metal salts (such as magnesium and calcium
salts).
Salts with a pharmaceutically unacceptable anion such as, for
example, trifluoroacetate likewise belong within the scope of the
invention as useful intermediates for the preparation or
purification of pharmaceutically acceptable salts and/or for use in
nontherapeutic, for example in vitro, applications.
The term "physiologically functional derivative" used herein refers
to any physiologically tolerated derivative of a compound of
formula I of the invention, for example, an ester which is able, on
administration to a mammal such as, for example, a human, to form
(directly or indirectly) a compound of formula I or an active
metabolite thereof.
Physiologically functional derivatives also include prodrugs of the
compounds of the invention, as described, for example, in H. Okada
et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be
metabolized in vivo to a compound of the invention. These prodrugs
may themselves have activity or not.
The compounds of the invention may also-exist in various
polymorphous forms, for example as amorphous and crystalline
polymorphous forms. All polymorphous forms of the compounds of the
invention belong within the scope of the invention and are a
further aspect of the invention.
All references hereinafter to "compound(s) of formula I" refer to
compound(s) of formula I as described above, and to the salts,
solvates and physiologically functional derivatives thereof as
described herein.
The amount of a compound of formula I necessary to achieve the
desired biological effect depends on a number of factors, for
example the specific compound chosen, the intended use, the mode of
administration and the clinical condition of the patient. The daily
dose is generally in the range from about 0.3 mg to 100 mg
(typically from about 3 mg to 50 mg) per day and per kilogram of
body weight, for example about 3-10 mg/kg/day. An intravenous dose
may be, for example, in the range from about 0.3 mg to 1.0 mg/kg,
which can suitably be administered as an infusion of about 10 ng to
100 ng per kilogram and per minute. Suitable infusion solutions for
these purposes may contain, for example, from about 0.1 ng to 10
mg, typically from about 1 ng to 10 mg, per milliliter. Single
doses may contain, for example, from about 1 mg to 10 g of the
active compound. Thus, ampoules for injections may contain, for
example, from about 1 mg to 100 mg, and single-dose formulations
which can be administered orally, such as, for example, capsules or
tablets, may contain, for example, from about 1.0 to 1000 mg,
typically from about 10 to 600 mg. For the therapy of the
abovementioned conditions, the compounds of formula I may be used
as the compound itself, but they may be in the form of a
pharmaceutical composition with an acceptable carrier. The carrier
is acceptable in the sense that it is compatible with the other
ingredients of the composition and is not harmful to the patient's
health. The carrier may be a solid or a liquid or both and is often
formulated with the compound as a single dose, for example as a
tablet, which may contain from about 0.05% to 95% by weight of the
active compound. Other pharmaceutically active substances may
likewise be present, including other compounds of formula 1. The
pharmaceutical compositions of the invention can be produced by one
of the known pharmaceutical methods, which may essentially consist
of mixing the ingredients with pharmacologically acceptable
carriers and/or excipients.
Pharmaceutical compositions of the invention include those suitable
for oral, rectal, topical, peroral (for example sublingual) and
parenteral (for example subcutaneous, intramuscular, intradermal or
intravenous) administration, although the most suitable mode of
administration depends in each individual case on the nature and
severity of the condition to be treated and on the nature of the
compound of formula I used in each case. Coated formulations and
coated slow-release formulations also belong within the framework
of the invention. Preference is given to acid- and gastric
juice-resistant formulations. Suitable coatings resistant to
gastric juice comprise cellulose acetate phthalate, polyvinyl
acetate phthalate, hydroxypropylmethylcellulose phthalate and
anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration may be in
the form of separate units such as, for example, capsules, wafers,
suckable tablets or tablets, each of which contain a defined amount
of the compound of formula l; as powders or granules, as solution
or suspension in an aqueous or nonaqueous liquid; or as an
oil-in-water or water-in-oil emulsion. These compositions may, as
already mentioned, be prepared by any suitable pharmaceutical
method which includes a step in which the active compound and the
carrier (which may consist of one or more additional ingredients)
are brought into contact. The compositions are generally produced
by uniform and homogeneous mixing of the active compound with a
liquid and/or finely divided solid carrier, after which the product
is shaped if necessary. Thus, for example, a tablet can be produced
by compressing or molding a powder or granules of the compound,
where appropriate with one or more additional ingredients.
Compressed tablets can be produced by tableting the compound in
free-flowing form such as, for example, a powder or granules, where
appropriate mixed with a binder, glidant, inert diluent and/or one
or more surface-active/dispersing agent(s) in a suitable machine.
Molded tablets can be produced by molding the compound which is in
powder form and is moistened with an inert liquid diluent in a
suitable machine.
Pharmaceutical compositions which are suitable for peroral
(sublingual) administration comprise suckable tablets which contain
a compound of formula I with a flavoring, normally sucrose and gum
arabic or tragacanth, and pastilles which comprise the compound in
an inert base such as gelatin and glycerol or sucrose and gum
arabic.
The pharmaceutical compositions suitable for parenteral
administration may comprise sterile aqueous preparations of a
compound of formula I, which may be isotonic with the blood of the
intended recipient. These preparations may be administered
intravenously, although administration may also take place by
subcutaneous, intramuscular or intradermal injection. These
preparations can be produced by mixing the compound with water and
making the resulting solution sterile and isotonic with blood.
Injectable compositions of the invention generally contain from
about 0.1 to 5% by weight of the active compound.
Pharmaceutical compositions suitable for rectal administration may
be in the form of single-dose suppositories. These can be produced
by mixing a compound of formula I with one or more conventional
solid carriers, for example cocoa butter, and shaping the resulting
mixture.
Pharmaceutical compositions suitable for topical use on the skin
may be in the form of an ointment, cream, lotion, paste, spray,
aerosol or oil. Carriers which can be used are petrolatum, lanolin,
polyethylene glycols, alcohols and combinations of two or more of
these substances. The active compound is generally present in a
concentration of from about 0.1 to 15% by weight of the
composition, for example from about 0.5 to 2%.
Transdermal administration is also possible. Pharmaceutical
compositions suitable for transdermal uses can be in the form of
single plasters which are suitable for long-term close contact with
the patient's epidermis. Such plasters suitably contain the active
compound in an aqueous solution which is buffered where
appropriate, dissolved and/or dispersed in an adhesive or dispersed
in a polymer. A suitable active compound concentration is about 1%
to 35% by weight, or about 3% to 15%. A possibility is for the
active compound to be released by electrotransport or iontophoresis
as described, for example, in Pharmaceutical Research, 2(6): 318
(1986).
The invention furthermore provides a process for preparing the
compounds of formula I which comprises obtaining the compounds of
formula I by proceeding in accordance with the reaction scheme
below: ##STR6##
To this end, compounds of formula A in which R1, R2, R4 and X have
the meanings given above are reacted with NaI in acetone with
heating at reflux for about 12 to 24 hours, giving a compound of
formula B.
The compound of formula B is reacted with a compound of formula C
in which n and m are each 0-5, giving a compound of formula E in
which R1, R2, R4, m, n and X have the meanings described above.
Here, (a) C is deprotonated at room temperature in an inert solvent
such as dimethylformamide or tetrahydrofuran using sodium hydride
and the n reacted at about 70.degree. C. with the halide, or (b)
component C is initially heated with dibutyltin oxide in toluene on
a water separator for a number of hours and then, with addition of
dimethylformamide, cesium fluoride and iodide B, converted into E
by stirring at room temperature for a number of hours, such as
between about 10 and 14 hours, preferably overnight.
The compound of formula E is, using a compound of formula D in
which Y is as described above, converted into a compound of formula
F in which R1, R2, R4, R5, X and Y have the meanings described
above. To form an ether bond, E is deprotonated, for example in a
mixture of dimethylformamide and tetrahydrofuran using a strong
base such as Na hydride at room temperature, and then alkylated
with a component D, often with addition of Na iodide.
The compound of formula F is converted into compounds of formula I
by hydrolyzing the ester function, for example by heating with
potassium hydroxide in an alcohol (ethanol, tert-butanol) and
releasing the carboxylic acid group of formula I by acidification.
This carboxylic acid group can be derivatized by customary methods
to a group of the formula --(C.dbd.O)--OR3, where R3 has the
meaning described above.
The compounds of formula I act favorably on metabolic disorders.
They have a positive effect on lipid and sugar metabolism and, in
particular, reduce the concentration of triglycerides and they are
suitable for preventing and treating type II diabetes and
arteriosclerosis.
The compounds can be administered alone or in combination with one
or more further pharmacologically active substances which, for
example, act favorably on metabolic disorders and are selected, for
example, from antidiabetics, antiadipose agents, antihypertensives
and active compounds for treating and/or preventing complications
caused by or associated with diabetes.
Suitable further pharmacologically active substances are:
All antidiabetics mentioned in chapter 12 of Rote Liste 2001. They
may be combined with the compounds of formula I according to the
invention for synergistic improvement of the effect. Administration
of the active compound combination may take place either by
separate administration of the active compounds to the patients or
in the form of combination products in which a plurality of active
compounds are present in one pharmaceutical preparation. Most of
the active compounds listed below are disclosed in USP Dictionary
of USAN and International Drug Names, US Pharmacopeia, Rockville,
Md. 2001.
Antidiabetics include insulin and insulin derivatives such as, for
example, Lantus.RTM. (see www.lantus.com) or HMR 1964, fast-acting
insulins (see U.S. Pat. No. 6,221,633), GLP-1 derivatives such as,
for example, those disclosed in WO 98/08871 of Novo Nordisk A/S,
and orally active hypoglycemic active compounds.
Orally active hypoglycemic active compounds include sulfonylureas,
biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones,
glucosidase inhibitors, glucagon antagonists, GLP-1 agonists,
potassium channel openers such as, for example, those disclosed in
WO 97/26265 and WO 99/03861 of Novo Nordisk ANS, insulin
sensitizers, inhibitors of liver enzymes involved in the
stimulation of gluconeogenesis and/or glycogenolysis, modulators of
glucose uptake, compounds which alter lipid metabolism, such as
antihyperlipidemic active compounds and antilipidemic active
compounds, compounds which reduce food intake, PPAR and PXR
agonists and active compounds which act on the ATP-dependent
potassium channel of beta cells.
In one embodiment of the invention, the compounds of formula I are
administered in combination with an HMG-CoA reductase inhibitor
such as simvastatin, fluvastatin, pravastatin, lovastatin,
atorvastatin, cerivastatin or rosuvastatin.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a cholesterol absorption inhibitor
such as, for example, ezetimibe, tiqueside or pamaqueside.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a PPAR gamma agonist such as, for
example, rosiglitazone, pioglitazone, JTT-501 or GI 262570.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a PPAR alpha agonist such as, for
example, GW 9578 or GW 7647.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a mixed PPAR alpha/gamma agonist
such as, for example, GW 1536, AVE 8042, AVE 8134, or AVE 0847, or
as described in PCT/US00/11833, PCT/US00/11490, or DE
10142734.4.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a fibrate such as, for example,
fenofibrate, clofibrate or bezafibrate.
In one embodiment of the invention, the compounds of formula I are
administered in combination with an MTP inhibitor such as, for
example, implitapide, BMS-201038 or R-103757.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a bile acid adsorption inhibitor
(see, for example, U.S. Pat. No. 6,245,744 or U.S. Pat. No.
6,221,897) such as, for example, HMR 1741.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a CETP inhibitor such as, for
example, JTT-705.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a polymeric bile acid adsorbent
such as, for example, cholestyramine or colesevelam.
In one embodiment of the invention, the compounds of formula I are
administered in combination with an LDL receptor inducer (see U.S.
Pat. No. 6,342,512) such as, for example, HMR1171 or HMR 1586.
In one embodiment of the invention, the compounds of formula I are
administered in combination with an ACAT inhibitor such as, for
example, avasimibe.
In one embodiment of the invention, the compounds of formula I are
administered in combination with an antioxidant such as, for
example, OPC-14117.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a lipoprotein lipase inhibitor
such as, for example, NO-1886.
In one embodiment of the invention, the compounds of formula I are
administered in combination with an ATP citrate lyase inhibitor
such as, for example, SB-204990.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a squalene synthetase inhibitor
such as, for example, BMS-188494.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a lipoprotein(a) lowering agent /
HDL enhancer such as, for example, Cl-1027 or nicotinic acid.
In one embodiment of the invention, the compounds of formula I are
administered in combination with a lipase inhibitor such as, for
example, orlistat.
In one embodiment of the invention, the compounds of formula I are
administered in combination with insulin.
In one embodiment, the compounds of formula I are administered in
combination with a sulfonylurea such as, for example, tolbutamide,
glibenclamide, glipizide or glimepiride.
In one embodiment, the compounds of formula I are administered in
combination with a biguanide such as, for example, mefformin.
In another embodiment, the compounds of formula I are administered
in combination with a meglitinide such as, for example,
repaglinide.
In one embodiment, the compounds of formula I are administered in
combination with a thiazolidinedione such as, for example,
troglitazone, ciglitazone, pioglitazone, rosiglitazone or the
compounds disclosed in WO 97/41097 of Dr. Reddy's Research
Foundation, such as
5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2
,4-thiazolidinedione.
In one embodiment, the compounds of formula I are administered in
combination with an .alpha.-glucosidase inhibitor such as, for
example, miglitol or acarbose.
In one embodiment, the compounds of formula I are administered in
combination with an active compound which acts on the ATP-dependent
potassium channel of beta cells, such as, for example, tolbutamide,
glibenclamide, glipizide, glimepiride or repaglinide.
In one embodiment, the compounds of formula I are administered in
combination with more than one of the aforementioned compounds, for
example in combination with a sulfonylurea and metformin, a
sulfonylurea and acarbose, repaglinide and metformin, insulin and a
sulfonylurea, insulin and metformin, insulin and troglitazone,
insulin and lovastatin, etc.
In a further embodiment, the compounds of formula I are
administered in combination with CART modulators (see.
"Cocaine-amphetamine-regulated transcript influences energy
metabolism, anxiety and gastric emptying in mice" Asakawa, A, et
al., Hormone and Metabolic Research (2001), 33(9), 554-558), NPY
antagonists (for example
N-{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}-naphthalene-1-
sulfonamide hydrochloride (CGP 71683A)), MC4 agonists (for example
N-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazoio[4,3-c]pyridi
n-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-1-amino-1,2,3,4-tetrahydronaphthalen
e-2-carboxamide (WO 01/91752)), orexin antagonists (for example
1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea
hydrochloride (SB-334867-A)), H3 agonists (for example
3-cyclohexyl-1-(4,4,
dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one
oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (for
example
[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren[4-yl]dipropylam
ine (WO 00/66585)), CRF BP antagonists (for example urocortin),
urocortin agonists, .beta.3 agonists (for example
1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-y
loxy)ethylamino]ethanol hydrochloride (WO 01/83451)), MSH
(melanocyte-stimulating hormone) agonists, CCK-A agonists (for
example
{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-thiazol-2-ylcar
bamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid
salt (WO 99/15525)); serotonin reuptake inhibitors (for example
dexfenfluramine), mixed serotoninergic and noradrenergic compounds
(for example WO 00/71549), 5HT agonists (for example
1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO
01/09111)), bombesin agonists, galanin antagonists, growth hormone
(for example human growth hormone), growth-hormone-releasing
compounds (tert-butyl
6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1
H-isoquinoline-2-carboxylate (WO 01/85695)), TRH agonists (see, for
example, EP 0 462 884), decoupling protein 2 or 3 modulators,
leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew
C.; Rozhavskaya-Arena, Marina; Grasso, Patricia, "Leptin agonists
as a potential approach to the treatment of obesity," Drugs of the
Future (2001), 26(9), 873-881), DA agonists (for example
bromocriptin or doprexin), lipase/amylase inhibitors (for example
WO 00/40569), PPAR modulators (for example WO 00/78312), RXR
modulators or TR .beta. agonists.
In one embodiment of the invention, the other active compound is
leptin; see, for example, "Perspectives in the therapeutic use of
leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema,
Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.
In one embodiment, the other active compound is dexamphetamine or
amphetamine.
In one embodiment, the other active compound is fenfluramine or
dexfenfluramine.
In a further embodiment, the other active compound is
sibutramine.
In one embodiment, the other active compound is orlistat.
In one embodiment, the other active compound is mazindol or
phentermine.
In one embodiment, the compounds of formula I are administered in
combination with dietary fiber materials, such as insoluble dietary
fiber materials (see, for example, carob/Caromax.RTM. (Zunft H J;
et al., Carob pulp preparation for treatment of
hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep.-Oct.), 18(5),
230-6). Caromax.RTM. is a carob-containing product from Nutrinova,
Nutrition Specialties & Food Ingredients GmbH, Industriepark
Hochst, 65926 Frankfurt/Main, Germany. Combination with
Caromax.RTM. is possible in one preparation or by separate
administration of compounds of formula I and Caromax.RTM..
Caromax.RTM. can moreover be administered in the form of foodstuffs
such as, for example, in bakery products or muesli bars.
It is self-evident that any suitable combination of the compounds
of the invention with one or more of the aforementioned compounds
and optionally one or more other pharmacologically active
substances is regarded as falling within the protection conferred
by the present invention. ##STR7## ##STR8##
This invention furthermore relates to the use of compounds of
formula I and their pharmaceutical compositions as PPAR ligand
receptor binders. The PPAR ligand receptor binders according to the
invention are suitable for use as agonists or antagonists of the
PPAR receptor.
Peroxisome-proliferator-activated receptors (PPAR) can be divided
into the three subtypes PPAR.alpha., PPAR.delta. and PPAR.sub.Y.
These are encoded by different genes (Motojima, Cell Structure and
Function, 18:267-277, 1993). In addition, there are two isotopes of
PPAR.sub.Y, PPAR.sub.Y1 and .sub.Y2. These two proteins differ in
the 30 NH.sub.2 -terminal amino acids and are the result of an
alternative use of promoters and different mRNA splicing
(Vidal-Puig, Jiminez, Linan, Lowell, Hamann, Hu, Spiegelman, Flier,
Moller, J. Clin. Invest., 97:2553-2561, 1996).
PPAR-modulated biological processes are processes modulated by
receptors or combinations of receptors which react to the PPAR
receptor ligands described in the present document. These processes
include, for example, plasma lipid transport and fatty acid
catabolism, regulation of insulin sensitivity and blood glucose
levels involved in hypoglycemia/hyperinsulinism (caused, for
example, by functional disorders of the pancrease beta-cells,
insulin-secreting tumors and/or autoimmune hypoglycemia owing to
autoantibodies against insulin, the insulin receptor or
autoantibodies having a stimulating action on pancrease
beta-cells), macrophage differentiation resulting in the formation
of atherosclerotic plaques, in inflammable reactions,
carcinogenesis, hyperplasia or adipocyte differentiation.
Adiposity is an excessive buildup of fatty tissue. Recent
investigations in this field have shown that PPAR.sub.Y plays a
central role in gene expression and differentiation of adipocytes.
Excess fatty tissue is associated with the development of serious
disorders such as, for example, non-insulin-dependent diabetes
mellitus (NIDDM), hypertension, disorders of the coronary arteries,
hyperlipidemia, adiposity and certain malignant syndromes. The
adipocytes can, by forming tumor necrosis factor a (TNF.alpha.) and
other molecules, also have an effect on glucose homeostasis.
Non-insulin-dependent diabetes mellitus (NIDDM) or type II diabetes
is the more frequent form of diabetes. About 90-95% of
hyperglycemia patients suffer from this form of the disease. What
is present in NIDDM is apparently a reduction of the mass of the
beta cells of the pancreas, a number of different disorders of
insulin secretion or reduced insulin sensitivity of the tissue. The
symptoms of this form of diabetes include tiredness, frequent
urination, thirst, blurred vision, frequent infections and slow
healing of wounds, diabetic nerve damage and kidney diseases.
Resistance against the metabolic effects of insulin is one of the
main features of non-insulin-dependent diabetes (NIDDM). Insulin
resistance is characterized by reduced uptake and conversion of
glucose in insulin-sensitive target organs such as, for example,
adipocytes and skeletal muscles, and by reduced inhibition of
hepatic gluconeogenesis. Functional insulin deficiency and the
absent suppression of hepatic gluconeogenesis by insulin leads to
hyperglycemia in the fasting state. The pancreas beta-cells
compensate for insulin resistance by increased secretion of
insulin. However, the beta-cells are not able to maintain this high
insulin output, so that the glucose-induced insulin secretion
decreases, resulting in a deterioration of glucose homeostasis and
finally in the development of manifest diabetes.
Hyperinsulinemia is likewise associated with insulin resistance,
hypertriglyceridemia and increased plasma concentrations of
low-density lipoproteins. Insulin resistance and hyperinsulinemia
combined with these metabolic disorders is called "syndrome X" and
is strongly associated with an increased risk of hypertension and
disorders of the coronary arteries.
Metformin is known to the person skilled in the art as an agent for
treating diabetes in humans (U.S. Pat. No. 3,174,901). The primary
action of metformin is reduced formation of glucose in the liver.
As is known, Troglitazone.RTM. acts primarily by improving the
ability of skeletal muscles to react to insulin and to take up
glucose. It is known that a combination therapy of metformin and
Troglitazone.RTM. can be used for treating diabetes-associated
disorders (DDT 3:79-88, 1998).
It has been observed that PPAR.sub.Y activators, such as
Troglitazone.RTM., convert cancerous tissue in liposarcoma (fat
tumors) into normal cells (PNAS 96:3951-3956, 1999). Furthermore,
it has been proposed that PPAR.sub.Y activators may be of benefit
in the treatment of breast cancer and intestinal cancer (PNAS
95:8806-8811,1998; Nature Medicine 4:1046-1052, 1998).
In addition, PPAR.sub.Y activators such as, for example,
Troglitazone.RTM. have also been used for treating polycystic
ovarial syndrome (PCO). This syndrome, which occurs in women, is
characterized by chronic anovulation and hyperandrogenism. Women
with this syndrome frequently also suffer from insulin resistance
and an increased risk of developing non-insulin-dependent diabetes
mellitus (Dunaif, Scott, Finegood, Quintana, Whitcomb, J. Clin.
Endocrinol. Metab., 81:3299, 1996).
Furthermore, it has recently been discovered that PPAR.sub.Y
activators increase the formation of progesterone and inhibit
steroid genesis in granulosa cell cultures and may therefore be
suitable for treating climacterium -(U.S. Pat. No. 5,814,647, Urban
etal., Sep. 29, 1998; B. Lorke et al., Journal of Endocrinology,
159, 429-39, 1998). Climacterium is defined as the syndrome of the
endocrine, somatic and psychological changes which occur in women
at the end of the reproductive phase.
Peroxisomes are cellular organelles involved in the control of the
redox potential and oxidative stress in cells by metabolizing a
large number of substrates such as, for example, hydrogen peroxide.
A number of disorders are associated with oxidative stress. Thus,
for example, inflammable reactions to tissue damage, pathogenesis
of emphysema, ischemia-associated organ damage (shock),
doxorubicin-induced heart damage, drug-induced hepatotoxicity,
atherosclerosis and lung damage caused by hyperoxia are in each
case associated with the formation of reactive oxygen species and
changes of the reductive capability of the cell. Accordingly, it
has been proposed that PPAR.alpha. activators regulate inter alia
the redox potential and the oxidative stress in cells and may be
useful for treating these disorders (Poynter et al., J. Biol. Chem.
273, 3283341, 1998).
It has also been found that PPAR.alpha. agonists inhibit NF.sub.K
B-mediated transcription and thus modulate various inflammatory
reactions, such as, for example, the enzyme paths of inducible
nitrous oxide synthase (NOS) and cyclooxygenase-2 (COX-2)
(Pineda-Torra, l. et al., 1999, Curr. Opinion in Lipidology, 10,
151-9) and can therefore be used for therapeutic interventions in a
large number of different inflammatory diseases and other
pathological conditions (Colville-Nash et al., Journal of
Immunology, 161, 978-84, 1998; Staels et al, Nature, 393, 790-3,
1998).
Peroxisome proliferators activate PPAR which, in turn, act as
transcription factors and cause differentiation, cell growth and
proliferation of peroxisomes. It is also presumed that PPAR
activators play a role in hyperplasia and carcinogenesis and change
the enzymatic properties of animal cells such as, for example,
rodent cells; however, these PPAR activators appear to have only
minimal negative effects on human cells (Green, Biochem. Pharm.
43(3):393, 1992). Activation of PPAR leads to a rapid increase of
gamma-glutamyl transpeptidase and -catalase.
PPAR.alpha. is activated by a number of medium-chain fatty acids
and long-chain fatty acids and is involved in the stimulation of
3-oxidation of fatty acids in tissues such as liver, heart,
skeletal muscle and brown fatty tissue (Issemann and Green, ibid.;
Beck et al., Proc. R. Soc. Lond. 247:83-87, 1992; Gottlicher et
al., Proc. Natl. Acad. Sci. USA 89:4653-4657, 1992).
Pharmacological PPAR.alpha. activators such as, for example,
fenofibrate, clofibrate, gemfibrozil and bezafibrate are likewise
involved in the considerable reduction of plasma triglycerides and
a moderate reduction of LDL cholesterol, and they are used for
treating hypertriglyceridemia, hyperlipidemia and adiposity. It is
known that PPAR.alpha. is also involved in inflammatory disorders
(Schoonjans, K., Current Opinion in Lipidology, 8, 159-66,
1997).
The human nuclear receptor PPAR.delta. has been cloned from a cDNA
library of human osteosarcoma cells and is described completely in
A. Schmidt et al., Molecular Endocrinology, 6:1634-1641 (1992). The
contents of this article are hereby incorporated by reference into
the present document. It may be pointed out that in the literature
PPAR.delta. is also referred to as PPAR.beta. and as NUC1, but all
of these names refer to the same receptor. Thus, in A. Schmidt et
al., Molecular Endocrinology, 6:1634-1641,1992, for example, the
receptor is referred to as NUC1. PPAR.delta. is found both in
embryonal and in adult tissue. It has been reported that this
receptor is involved in the regulation of the expression of some
fat-specific genes and therefore plays a role in the process of
adipogenesis (Amri, E. et al., J. Biol. Chem. 270,
2367-71,1995).
It is known that atherosclerotic disorders are caused by a number
of factors such as, for example, hypertension, diabetes, low
concentrations of high-density lipoproteins (HDL) and high
concentrations of low-density lipoproteins (LDL). In addition to
reducing the risks by acting on the concentration of the plasma
lipids and other risk factors, PPAR.alpha. agonists have direct
atheroprotective actions (Frick, M. H. et al., 1997, Circulation
96:2137-2143, de Faire et al., 1997, Cardiovasc. Drugs Ther. 11
Suppl. 1:257-63).
It has recently been found that PPAR.delta. agonists are useful for
increasing HDL level and are therefore suitable for treating
atherosclerotic disorders (Leibowitz et al., WO 97/28149).
Atherosclerotic disorders include vascular disorders, coronary
heart disease, cerebrovascular disorders and disorders of the
peripheral vessels. Coronary heart disease includes death by
coronary heart disease, myocardial infarction and coronary
revascularization. Cerebrovascular diseases include ischemic and
hemorrhagic infarcts and transient ischemic attacks.
PPAR.sub.Y subtypes are involved in the activation of adipocyte
differentiation and do not play any role in the stimulation of
peroxysome proliferation in the liver. Activation of PPAR.sub.Y
contributes to adipocyte differentiation by activating the
adipocyte-specific gene expression (Lehmann, Moore, Smith-Oliver,
Wilkison, Willson, Kliewer, J. Biol. Chem., 270:12953-12956,1995).
The DNA sequences of the PPAR.sub.Y subtypes are described in
Elbrecht et al., BBRC 224; 431-437 (1996). Although peroxysome
proliferators including fibrates and fatty acids activate the
transciptory activity of PPARs, only prostaglandin J.sub.2
derivatives such as the arachidonic metabolite
15-deoxy-delta.sup.12, 14-prostaglandin J.sub.2 (15d-PGJ.sub.2)
have been identified as natural ligands specific for the PPAR.sub.Y
subtype which also binds to thiazolidinediones. This prostaglandin
activates PPAR.sub.Y -dependent adipogenesis, but activates
PPAR.alpha. only at high concentrations (Formann, Tontonoz, Chen,
Brun, Spiegelman, Evans, Cell, 83:803-812, 1995; Kliewer, Lenhard,
Wilson, Patel, Morris, Lehmann, Cell, 83:813-819, 1995). This is a
further indication that the subtypes of the PPAR family differ in
their pharmacological reaction to ligands.
From this, it can be concluded that compounds which activate
PPAR.alpha. or both PPAR.alpha. and PPAR.sub.Y have to be effective
hypotriglyceridemic drugs which can be used for treating
atherosclerosis-associated dislipidemia, non-insulin-dependent
diabetes mellitus, syndrome X (Staels, B. et al., Curr. Pharm.
Des., 3 (1),1-4 (1997)) and familial combined hyperlipidemia (FCH).
Syndrome X is characterized by a first insulin-resistant stage
which causes hyperinsulinemia, dyslipidemia and reduced glucose
tolerance and which can progress to non-insulin-dependent diabetes
mellitus (type II diabetes) characterized by hyperglycemia. FCH is
characterized by hypercholesterolemia and hypertriglyceridemia in
the same patient and in the'same family.
The present invention relates to compounds of formula I suitable
for modulating PPAR receptors, and for a number of other related
pharmaceutical applications.
The compounds of formula I are suitable for treating dyslipidemia,
insulin resistance, type I and type II diabetes, disturbed glucose
tolerance, syndrome X, obesity, eating disorders, thromboses,
inflammations, cardiomyopathy and for protecting beta-cells and
protection against fatty acid oxidation (see, for example,
Jean-Charles Fruchart, Bart Staels and Patrick Duriez: PPARS,
Metabolic Disease and Atherosclerosis, Pharmacological Research,
Vol. 44, No. 5, 2001; Sander Kersten, Beatrice Desvergne &
Walter Wahli: Roles of PPARs in health and disease, NATURE, VOL
405, MAY 25, 2000; Ines Pineda Torra, Giulia Chinetti, Caroline
Duval, Jean-Charles Fruchart and Bart Staels: Peroxisome
proliferator-activated receptors: from transcriptional control to
clinical practice, Curr Opin Lipidol 12: 2001, 245-254).
The activity of the compounds was tested as follows:
To analyze the effectiveness of substances which bind to human
PPAR.alpha., activating it in agonistic manner, a stable
transfected HEK cell line (HEK=human embryo kidney) designated here
as "PPAR.alpha. reporter cell line" is used.
The activity of PPAR.alpha. agonists is determined in a three-day
test, described below:
Day 1
The PPAR.alpha. reporter cell line is cultivated up to 80%
confluence in DMEM medium (#41965-039, Life Technologies) with the
following additives: 10% cs-FCS (fetal calf serum, #SH-30068.03,
Hyclone), antibiotics (0.5 mg/ml of zeozin [#R250-01, Invitrogen],
0.5 mg/ml of G418 [#10131-019, Life Technologies], 1% penicillin
streptomycin solution [#15140-031, Life Technologies]) and 2 mM of
L-glutamine (#25030-032, Life Technologies). Cultivation is carried
out in standard cell culture bottles (#33111, Becton Dickinson) in
a cell culture incubator at 37.degree. C. and 5% CO.sub.2. The 80%
confluent cells are washed once with 30 ml of PBS (#141-090- 094,
Life Technologies), treated with 2 ml of trypsin solution
(#25300-054, Life Technologies) at 37.degree. C. for 2 min, taken
up in 5 ml of the medium described above and counted in a cell
counter. After dilution to 500,000 cells/ml, in each case 100,000
cells are sown into each well of a 96-well microtiter plate having
a clear plastic bottom (#3610, Corning Costar). The plates are
incubated in a cell incubator at 37.degree. C. and 5% CO.sub.2 for
24 h.
Day 2
The PPAR.alpha. agonists to be tested are dissolved in DMSO at a
concentration of 10 mM. This stock solution is diluted in
Phenol-Red-free DMEM medium (#21063-029, Life Technologies) to
which 5% of cs-FCS (#SH-30068.03, Hyclone), 2 mM of L-glutamine
(#25030-032, Life Technologies) and the antibiotics described above
(zeozin, G418, penicillin and streptomycin) had been added.
Test substances are usually tested at 11 different concentrations
(10 .mu.M; 3.3 .mu.M; 1 .mu.M; 0.33 .mu.M; 0,1 .mu.M; 0.033 .mu.M;
0.01 .mu.M; 0.0033 .mu.M; 0.001 .mu.M; 0.00033 .mu.M and 0.0001
.mu.M). More potent compounds are tested in concentration ranges of
from 1 .mu.M to 10 pM or 100 nM to 1 pM. From each well, the medium
of the PPAR.alpha. reporter cell line sown on day 1 is completely
removed by aspiration, and immediately, the test substances diluted
in medium are added to the cells. Dilution and addition of the
substances can be carried out using a robot (Beckman Biomek 2000).
The end volume of the test substances diluted in medium is 100
.mu.l per well of a 96-well plate. The DMSO concentration in the
assay is always below 0.1% v/v to prevent cytotoxic effects of the
solvent.
To demonstrate that the assay is working in each individual plate,
a standard PPAR.alpha. agonist, which is also diluted to 11
different concentrations, is added to each plate. The test plates
are incubated in an incubator at 37.degree. C. and 5% CO.sub.2 for
24 h.
Day 3
The PPAR.alpha. receptor cells treated with the test substances are
removed from the incubator and frozen at -20.degree. C. for 1 h to
improve cell lysis. After the plates have thawed (thawing at room
temperature for at least 30 min), 50 .mu.l of buffer 1 (Luc-Screen
kit #LS1000, PE Biosystems Tropix) are pipetted into each well and
the plates are then transferred into an apparatus for measuring
luminescence, fitted with a pipetting unit (Luminoscan Ascent,
LabSystems). The luciferase reaction in the measurement apparatus
is started by pipetting 50 .mu.l of buffer 2 (Luc-Screen kit
#LS1000, PE Biosystems Tropix) into each well of the 96-well plate.
Addition of buffer to the individual wells is carried out in
defined and identical time intervals following the instructions of
the manufacturer (LabSystems). All samples are measured exactly 16
min after addition of buffer 2. Measurement time is 10 sec per
sample.
The crude data of the apparatus for measuring luminescence are
exported into a Microsoft Excel file. Dose-activity curves and
EC.sub.50 values are calculated using the program XL.Fit according
to the instructions of the manufacturer (IDBS).
The results for the activity of the compounds of formula I
according to the invention are listed in Table I below:
TABLE I Example No. EC50 PPAR.alpha. [nM] I 1 II 0.3 IV 0.3 VII 4 X
0.5 XIX 16 XXIV 0.9 XXV 13 XXVIII 14 XXIX 32 XXXII 0.97 XXXIV 0.82
XXXVI 0.62 XXXVIII 0.57 XLI 0.6 XLIII 0.58 XLIV 0.93 XLV 10 XLVI
0.56 XLVII 1.1
It is evident from Table I that the compounds of formula I
according to the invention activate the PPAR.alpha. receptor, thus
effecting, analogously to clinically used fibrates, a lowering of
the triglyceride concentration in the organism (see, for example,
J.-Ch. Fruchard et al.: PPARS, Metabolic Disease and
Atherosclerosis, Pharmacological Research, Vol. 44, No. 5, 2001; S.
Kersten et al.: Roles of PPARs in health and disease, NATURE, VOL
405, MAY 25, 2000; I. Pineda et al.: Peroxisome
proliferator-activated receptors: from transcriptional control to
clinical practice, Curr Opin Lipidol 12: 2001, 245-254).
The examples given below serve to illustrate the invention, but
without limiting it. Any measured melting points or decomposition
points (m.p.) are uncorrected and, in general, depend on the
heating rate.
EXAMPLE I
##STR9##
3-[2-(4-Fluorophenyl)oxazol4-ylmethoxy]cyclohexanol 3
##STR10##
With ice-cooling, initially 2.25 g of an 80 percent suspension of
sodium hydride and then 5.8 g of 1,3-cyclohexanediol were added to
a mixture of 50 ml of dimethylformamide and 50 ml of
tetrahydrofuran. The mixture was stirred at about 25.degree. C. for
3 hours. 10.5 g of 4-chloromethyl-2-(4-fluorophenyl)oxazole (1) was
then added, the mixture was heated at 70.degree. C. and the
reaction was monitored by thin-layer chromatography. After the
reaction ended, the mixture was poured into ice-water and extracted
with ethyl acetate. The organic phase was separated off, dried and
concentrated and the residue was purified on silica gel by flash
chromatography (ethyl acetate/n-heptane=1:1). This gave the alcohol
3 as an oil. C.sub.16 H18FNO3 (291.33) MS(ESI): 292
(M+H.sup.+).
Methyl
2-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-6-methylbenzoate
##STR11##
With ice-cooling, 0.3 g of a sodium hydride suspension (80%) were
introduced into a mixture of 10 ml of dimethylformamide and 20 ml
of tetrahydrofuran. 1 g of alcohol 3 in 5 ml of tetrahydrofuran was
then added, and the mixture was stirred at room temperature for 1
hour. 0.8 g of bromide 4 was then added, and the mixture was
stirred at room temperature and with monitoring by TLC for 3-5
hours until the conversion was substantially complete. The mixture
was poured into ice-water and extracted 3 times with ethyl acetate,
the organic phase was washed with 20 ml portions of water, dried
over sodium sulfate and concentrated under reduced pressure at 20
mbar for approximately 1 hour, and the residue was purified by
silica gel chromatography (ethyl acetate:n-heptane=1:2). This gave
the methyl ester 5 as an oil. C.sub.26 H.sub.28 FNO.sub.5 (453.52)
MS(ESI): 454 (M+H.sup.+).
2-{3-[2-(4-Fluorophenyl)oxazola4-ylmethoxy]cyclohexyloxy}-6-methylbenzoic
Acid 6
##STR12##
2 g of ester 5 were heated at reflux in 150 ml of tert-butanol and
24 ml of 50 percent aqueous potassium hydroxide solution for 6
hours. 4/5 of the butanol was removed under reduced pressure and
the mixture was diluted with water and acidified with ice-cooling.
The product was extracted with dichloromethane, dried over sodium
sulfate and concentrated under reduced pressure, giving, by
filtration of the residue through silica gel (CH.sub.2 Cl.sub.2
/MeOH=20:1), the acid 6 C.sub.25 H.sub.26 FNO.sub.5 (432.42)
MS(ESI): 433 (M+H.sup.+).
EXAMPLE II
##STR13##
2-(4-Fluorophenyl)-4-iodomethyloxazole 2
##STR14##
At 120.degree. C., 31 g (123 mmol) of p-fluorobenzamide and 33 g
(123 mmol) of 1,3-dichloroacetone were stirred in the absence of a
solvent for 2 hours. After cooling to room temperature, the product
was dissolved in 250 ml of ethyl acetate. This solution was diluted
with 400 ml of n-heptane and washed 3 times with saturated NaCl
solution. The organic phase was filtered through 250 ml of silica
gel, and the filter pad was then washed with 200 ml of
n-heptane/ethyl acetate (4:1). The solvent was distilled off,
giving 4-chloromethyl-2-(4-fluorophenyl)oxazole 1 as crude product.
This was dissolved in 650 ml of acetone, and 90 g of NaI were then
added. The mixture was then heated at reflux for 16 hours, most of
the solvent was then removed and the solid residue was suspended in
200 ml of n-heptane/ethyl acetate (1:1) and filtered through 200 ml
of silica gel. The precipitate was washed with 500 ml of
n-heptane/ethyl acetate (1:1), and the organic phase was
concentrated. On concentration, the iodide 2 began to crystallize
as white crystals. TLC n-heptane/ethyl acetate (6:1) R.sub.f 0.4
for 2 and R.sub.f =0.35 for 1. C.sub.10 H.sub.7 FINO (303.08)
MS(ESI): 304 (M+H.sup.+). ##STR15##
10.8 g (93.1 mmol) of cis/trans-1,3-cyclohexanediol and 15.4 g
(61.8 mmol) of dibutyltin oxide were heated in 800 ml of toluene on
a water separator for 5 hours. 400 ml of toluene were distilled
off, and the mixture was then allowed to cool to room temperature,
and 280 ml of dry DMF, 15 g (49.5 mmol) of 2 and 12.7 g (80.1 mmol)
of dry CsF were then added successively. The heterogeneous mixture
was stirred at room temperature for 20 hours (TLC control starting
material 2). 200 ml of ethyl acetate were added, and the mixture
was washed three times with saturated NaCl solution. The organic
phase was filtered through 150 ml of silica gel and concentrated.
Following addition of n-heptane/ethyl acetate (6:1), the residue
crystallized. Further recrystallization from n-heptane/ethyl
acetate gave the product 3a (mixture of cis-enantiomers). The
mixture of trans-enantiomers 3b was obtained from the mother liquor
after concentration and chromatography. TLC n-heptane/ethyl acetate
(1:1). R.sub.f 3a (cis)=0.2, R.sub.f 3b (trans)=0.3. C.sub.16
H.sub.18 FNO.sub.3 (291.33) MS(ESI): 292 (M+H.sup.+).
The pair of enantiomers 3a was separated by chiral HPLC. The
dextrorotatory (+)-enantiomer (+)3a eluted first, followed by the
levorotatory (-)-enantiomer (-)3a (Chiralpak AD 250 .times.4.6;
acetonitrile/methanol (9:1)).
The absolute stereochemistry was assigned by X-ray structural
analysis of the camphanic acid esters of the separated
diastereomers 3.
Methyl
cis-2-(3-(2-(4-fluorophenyl)oxazol-4-ylmethoxy)cyclohexyloxymethyl)-6-meth
ylbenzoate 5b
##STR16##
1.05 g (3.6 mmol) of (-)3a, 1.3 g (5.4 mmol) 4 and 130 mg of Kl
were dissolved in 12 ml of dry DMF. 140 mg (5.7 mmol) of 95% NaH
were added, and the mixture was then stirred at room temperature
for 1 hour. To achieve better yields with respect to the starting
material (-)3a, 2 more times, the same amount of 4 and NaH were
added, and the mixture was in each case stirred for 1 hour. The
mixture was then allowed to stand overnight. The reaction solution
was diluted with 150 ml of ethyl acetate and poured into 50 ml of
water. The mixture was washed 2 more times with NaCl solution, and
the organic phase was then filtered through silica gel and
concentrated, and the residue was purified by flash chromatography
(n-heptane/ethyl acetate, 1:1). This gave 5b as a colorless
amorphous solid. TLC n-heptane-ethyl acetate (1:1). R.sub.f =0.5.
C.sub.26 H.sub.28 FNO.sub.5 (453.52) MS(ESI): 454 (M+H.sup.+).
(+)-cis-2-(3-(2-(4-Fluorophenyl)oxazol4-ylmethoxy)cyclohexyloxymethyl)-6-me
thylbenzoic Acid 6b
##STR17##
4.2 g (9.2 mmol) of 5b were dissolved in 120 ml of t-BuOH. 50 ml of
50% aq. KOH were added, and the mixture was then boiled at
100.degree. C. for 24 hours. For work-up, the mixture was allowed
to cool and then diluted with 100 ml of ethyl acetate. The aqueous
phase was made slightly acidic by addition of 2 N aqueous HCl and
extracted 2 more times with 100 ml of ethyl acetate. The organic
phase was dried over MgSO.sub.4, filtered and concentrated, and the
residue was purified by flash chromatography (methylene
chloride/methanol/conc. ammonia, 30/5/1). This gave 6b as a white
amorphous solid. TLC (methylene chloride/methanol/conc. ammonia,
30/5/1). R.sub.f =0.3. Recrystallization from toluene. C.sub.25
H.sub.26 FNO.sub.5 (432.42) MS(ESI): 433 (M+H.sup.+).
EXAMPLE III
##STR18##
(-)-cis-2-{3-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-m
ethyl-benzoic Acid 6a
Using (+)3a and methyl 2-bromomethyl-6-methylbenzoate 4 as starting
materials in the procedure of Example I gave the product 6a of
molecular weight 432.42 (C.sub.25 H.sub.26 FNO.sub.5); MS(ESI): 433
(M+H.sup.+).
EXAMPLE IV
##STR19##
cis-2-(3-(2-(4-Methoxyphenyl)oxazol-4-ylmethoxy)cyclohexyloxymethyl)-6-meth
ylbenzoic Acid 7b
170 mg (0.39 mmol)of6b were heated in 4 ml of 5.6 M NaOMe/MeOH
solution at an oil bath temperature of 120.degree. C. for 20 hours.
Ethyl acetate and 2 N HCl were added, and the mixture was then
worked up analogously to the synthesis of 6b. This gave 7b as a
colorless amorphous solid. TLC: (methylene chloride/-methanol/conc.
ammonia, 30/5/1). R.sub.f.about.0.3. C.sub.26 H.sub.29 NO.sub.6
(451.52) MS(ESI): 452 (M+H.sup.+).
In the same manner, 6a gave the stereoisomeric 7a: ##STR20##
TLC: (methylene chloride/methanol/conc. ammonia, 30/5/1).
R.sub.f.about.0.3. C.sub.26 H.sub.29 NO.sub.6 (451.52) MS(ESI): 452
(M+H.sup.+).
EXAMPLE V (11a) and EXAMPLE VI (11b)
##STR21##
cis-3-(2-Phenyloxazol-4-ylmethoxy)cyclohexanol 12a,b
##STR22##
1,3-Cyclbhexanediol and 4-iodomethyl-2-phenyloxazole gave the
racemate 12 of molecular weight 273.33 (C.sub.16 H.sub.19
NO.sub.3); MS(ESI): 274 (M+H.sup.+).
The enantiomers were separated by HPLC on a chiral column. The
(+)-enantiomer 12a eluted first, followed by the (-)-enantiomer 12b
(Chiralpak OD 250.times.4.6;
n-heptane:ethanol:acetonitrile=110:2:1+0.05% trifluoroacetic
acid).
Methyl
cis-2-methyl-6-[3-(2-phenyloxazol-4-ylmethoxy)cyclohexyloxymethyl]-benzoat
e 13a
##STR23##
12a and methyl 2-bromomethyl-6-methylbenzoate gave 13a of molecular
weight 435.52 (C.sub.26 H.sub.29 NO.sub.5); MS(ESI): 436
(M+H.sup.+).
Methyl cis-2-methyl-6-[3-(2-phenyloxazol-4-yl
methoxy)cyclohexyloxymethyl]-benzoate 13b
##STR24##
12b and methyl 2-bromomethyl-6-methylbenzoate gave 13b of molecular
weight 435.52 (C.sub.26 H.sub.29 NO.sub.5); MS(ESI): 436
(M+H.sup.+).
Cis-2-Methyl-6-[3-(2-phenyloxazol4-ylmethoxy)cyclohexyloxymethyl]benzoic
Acid 11a
Hydrolysis of 13a gave 11a of molecular weight 421.50 (C.sub.25
H.sub.27 NO.sub.5); MS(ESI): 422 (M+H.sup.+).
Cis-2-Methyl-6-[3-(2-phenyloxazola4-ylmethoxy)cyclohexyloxymethyl]benzoic
Acid 11b
Analogously by hydrolysis, 13b gave 11b of molecular weight 421.50
(C.sub.25 H.sub.27 NO.sub.5); MS(ESI): 422 (M+H.sup.+).
EXAMPLE VII (14a) and EXAMPLE VIII (14b)
##STR25##
Cis-3-(2-p-Tolyloxazol-4-ylmethoxy)cyclohexanol 15a,b
##STR26##
Cyclohexanediol and 4-iodomethyl-2-p-tolyloxazole gave the racemate
15 of molecular weight 287.36 (C.sub.17 H.sub.21 NO.sub.3);
MS(ESI): 288 (M+H.sup.+).
Separation of the enantiomers was carried out by HPLC on a chiral
column. The (+)-enantiomer 15a eluted first, followed by the
(-)-enantiomer 15b (Chiralpak OD250.times.4.6;
n-heptane:ethanol:acetonitrile=110:5:1+0.05% trifluoroacetic
acid).
Methyl
cis-2-methyl-6-[3-(2-p-tolyloxazol4-ylmethoxy)cyclohexyloxymethyl]-benzoat
e 16a
##STR27##
15a and methyl 2-bromomethyl-6-methylbenzoate gave 16a of molecular
weight 449.55 (C.sub.27 H.sub.31 NO.sub.5); MS(ESI): 450
(M+H.sup.+).
Methyl
cis-2-methyl-6-[3-(2-p-tolyloxazol4-ylmethoxy)cyclohexyloxymethyl]benzoate
16b
##STR28##
15b and methyl 2-bromomethyl-6-methylbenzoate gave 16b of molecular
weight 449.55 (C.sub.27 H.sub.31 NO.sub.5); MS(ESI): 450
(M+H.sup.+).
Cis-2-Methyl-6-[3-(2-p-tolyloxazol4-ylmethoxy)cyclohexyloxymethyl]benzoic
Acid 14a
16a gave 14a of molecular weight 435.52 (C.sub.26 H.sub.29
NO.sub.5); MS(ESI): 436 (M+H.sup.+).
Cis-2-Methyl-6-[3-(2-p-tolyloxazla4-ylmethoxy)cyclohexyloxymethyi]benzoic
Acid 14b
16b gave the product 14b of molecular weight 435.52,(C.sub.26
H.sub.29 NO.sub.5); MS(ESI): 436 (M+H.sup.+).
EXAMPLE IX (17a) and EXAMPLE X (17b)
##STR29##
Cis-3-[2-(4-Fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexanol
18a,b
##STR30##
Cyclohexanediol and 2-(4-fluorophenyl)-4-iodomethyl-5-methyloxazole
gave the racemate 18 of molecular weight 305.35 (C.sub.17 H.sub.20
FNO.sub.3); MS(ESI): 306 (M+H.sup.+).
The enantiomers were separated by HPLC on a chiral column. The
(+)-enantiomer 18a eluted first, followed by the (-)-enantiomer 18b
(Chiralpak OD 250.times.4.6;
n-heptane:ethanol:acetonitrile=110:2:1+0.05% trifluoroacetic
acid).
Methyl
cis-2-{3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethy
l}-6-methylbenzoate 19a
##STR31##
18a and methyl 2-bromomethyl-6-methylbenzoate gave 19a of molecular
weight 467.54 (C.sub.27 H.sub.30 FNO.sub.5); MS(ESI): 468
(M+H.sup.+).
Methyl
cis-2-{3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyloxymeth
yl}-6-methylbenzoate 19b
##STR32##
18b and methyl 2-bromomethyl-6-methylbenzoate gave 19b of molecular
weight 467.54 (C.sub.27 H.sub.30 FNO.sub.5); MS(ESI): 468
(M+H.sup.+).
Cis-2-(3-[2-(4-Fluorophenyl
)-5-methyloxazol4-ylmethoxy]cyclohexyloxymethyl}-6-methylbenzoic
Acid 17a
Hydrolysis of 19a gave 17a of molecular weight 453.52 (C.sub.26
H.sub.28 FNO5); MS(ESI): 454 (M+H.sup.+).
Cis-2-{3-[2-(4-Fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexyloxymethyl}
-6-methylbenzoic Acid 17b
Analogously by hydrolysis, 19b gave 17b of molecular weight 453.52
(C.sub.26 H.sub.28 FNO.sub.5); MS(ESI): 454 (M+H.sup.+).
EXAMPLE XI (20) and EXAMPLE XII (21)
##STR33##
Ethyl 5-bromomethyl-2-methylbenzoate 22 and ethyl
2-bromomethyl-5-methylbenzoate 23
##STR34##
A solution of 3.5 g of ethyl 2,5-dimethylbenzoate, 3.15 g of
N-bromosuccinimide and 100 ml of carbon tetrachloride was, for 3
hours, heated under reflux and irradiated with a 300 watt
photolamp. The resulting precipitate was filtered off and the
concentrated filtrate was chromatographed on silica gel. This gave
an approximately 2:3 (22:23) mixture of the regioisomeric benzyl
bromides 22 and 23 of molecularweight 257.13 (C.sub.11 H.sub.13
BrO.sub.2); MS (ESI): 257 (M+H.sup.+). Ethyl
rac-cis-5-{3-[2-(4-fluorophenyl)oxazol4-ylmethoxy]cyclohexyloxymethyl}-2-m
ethylbenzoate 24 and ethyl
rac-cis-2-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxymethyl}-5-
methylbenzoate 25. ##STR35##
At 0.degree. C., a solution of 150 mg of
rac-cis-3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]-cyclohexanol 3a in
0.5 ml of dimethylformamide was added dropwise to a suspension of
40 mg of sodium hydride (55-65% in paraffin oil) in 1 ml of
dimethylfdrmamide. After the evolution of gas ceased, 198 mg of 2:3
mixture of ethyl 5-bromomethyl-2-methylbenzoate 22 and ethyl
2-bromomethyl-5-methyl-benzoate 23 were added. After 30 minutes at
0.degree. C., the mixture was allowed to react for a further 1 hour
at room temperature. The mixture was poured into an ammonium
chloride solution and extracted twice with MTBE. The extracts were
dried over magnesium sulfate, filtered and concentrated using a
rotary evaporator, and the product was then purified by silica gel
chromatography (mobile phase: n-heptane/ethyl acetate 3:1). This
gives the faster eluting product ethyl
rac-cis-2-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxymethyl}-5-
methylbenzoate 25 of molecular weight 467.54 (C.sub.27 H.sub.30
FNO.sub.5); MS (ESI): 468 (M+H.sup.+).
Also isolated was the later eluting product ethyl
rac-cis-5-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxymethyl}-2-
methylbenzoate 24 of molecular weight 467.54 (C.sub.27 H.sub.30
FNO.sub.5); MS (ESI): 468 (M+H.sup.+).
Rac-cis-5-{3-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxymethyl}-2-m
ethylbenzoic Acid 20
A suspension of 47 mg of ethyl
rac-cis-5-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxymethyl}-2-
methylbenzoate 24, 2 ml of 1,1-dimethylethanol and 50% (w/w)
potassium hydroxide was heated at 85.degree. C. (oil bath) for 2
hours. The pH was adjusted to 3 using dilute hydrochloric acid and
the mixture was extracted twice with MTBE. The extracts were dried
over magnesium sulfate, filtered and concentrated on a rotary
evaporator, and the product was then purified by chromatography.
This gave the product 20 of molecular weight 439.49 (C.sub.25
H.sub.26 FNO5); MS (ESI): 440 (M+H.sup.+).
Using a different starting material in the procedure for making 20:
rac-cis-2-{3-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxymethyl}-5-m
ethylbenzoic acid 21 was prepared from ethyl
rac-cis-2-{3-[2-(4-fluorophenyl)oxazol4-ylmethoxy]cyclohexyloxymethyl}-5-m
ethylbenzoate 25.
EXAMPLE XIII
Rac-trans-2-{3-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxymethyl}-6
-methylbenzoic acid 26
##STR36##
rac-trans 3b and methyl 2-bromomethyl-6-methylbenzoate gave the
product 26 of molecular weight 439.49 (C.sub.25 H.sub.26
FNO.sub.5); MS(ESI): 440 (M+H.sup.+).
EXAMPLE XIV
##STR37##
5-(2-(4-Fluorophenyl)oxazol-4-ylmethoxyrmethyl)-1,3-dioxan-5-ylmethanol
28
##STR38##
1.0 g (6.7 mmol) of 5-hydroxymethyl-1,3-dioxan-5-ylmethanol and 0.5
g (16.5 mrpol) of 2 were dissolved in 20 ml of dry DMF. 300 mg of
55% NaH in paraffin oil were added, and the mixture was then
stirred at room temperature for 1 hour. Work-up-was carried out
analogously to the synthesis of compound 5b. This gave 28 as a
white amorphous solid. TLC (n-heptane/ethyl acetate 1:2). R.sub.f
=0.4. C.sub.16 H.sub.18 FNO.sub.5 (323.33) MS(ESI) 324.2
(M+H.sup.+).
Methyl
2-{5-[2-(4-fluorophenyl)oxazol4-ylmethoxymethyl]-1,3-dioxan-5-ylmethoxymet
hyl}-6-methylbenzoate 29
##STR39##
Using 28 and 4 as starting materials in the synthesis procedure of
5b of Example II gave compound 29.
2-{5-[2-(4-Fluorophenyl)oxazol4-ylmethoxymethyl]-1,3-dioxan-5-ylmethoxymeth
yl}-6-methylbenzoic Acid 27
Using 29 as a starting material in the synthesis procedure for 6b
of Example II gave compound 27 by hydrolysis.
EXAMPLE XV
##STR40##
2-{1-[2-(4-Fluorophenyl)oxazol4-ylmethoxymethyl]cyclohex-3-enylmethoxymethy
l}-6-methylbenzoic Acid 31
using (1-hydroxymethylcyclohex-3-enyl)methanol,iodide 2 and bromide
4 as starting in the procedure of Example XIV, gave the product 31
of molecular weight 465.53 (C.sub.27 H.sub.28 FNO.sub.5); MS(ESI):
466 (M+H.sup.+).
EXAMPLE XVI
##STR41##
2-{1-[2-(4-Fluorophenyl)oxazol-4-ylmethoxymethyl]cyclohexylmethoxymethyl}-6
-methylbenzoic Acid 32
Using (1-hydroxymethylcyclohexyl)methanol, iodide 2, and bromide 4
as reactants in the procedure of Example XIV gave the product 32 of
molecular weight 467.53 (C.sub.27 H.sub.30 FNO.sub.5); MS(ESI): 468
(M+H.sup.+).
EXAMPLE XVII
##STR42##
Rac-trans-2-{2-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxymethyl}-6
-methylbenzoic Acid 33
Using trans-1,2-dihydroxycyclohexanol, iodide 2 and bromide 4 as
starting materials in the synthesis procedure of Example XIV, gave
the desired product 33 of molecular weight 439.49 (C.sub.25
H.sub.26 FNO.sub.5); MS(ESI): 440 (M+H.sup.+).
EXAMPLE XVIII
##STR43##
2-{4-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-methylben
zoic Acid 34
1,4-Cyclohexanediol, iodide 2 and bromide 4 gave product 34 of
molecular weight 439.49 (C.sub.25 H.sub.26 FNO.sub.5); MS(ESI): 440
(M+H.sup.+).
EXAMPLE XIX
##STR44##
2-{4-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]cyclopent-2-enyloxymethyl}-6-met
hylbenzoic Acid 35
Cyclopent-2-ene-1,4-diol, iodide 2 and bromide 4 gave the product
35 of molecular weight 423.45 (C.sub.24 H.sub.22 FNO.sub.5);
MS(ESI): 424 (M+H.sup.+).
EXAMPLE XX
##STR45##
2-{5-[2-(4-Fluorophenyl)oxazol4-ymethoxy]cyclooctyloxymethyl}-6-methylbenzo
ic Acid 36
1,5-Cyclooctanediol, iodide 2 and bromide 4 gave product 36 of
molecular weight 467.54 (C.sub.27 H.sub.30 FNO.sub.5); MS(ESI): 468
(M+H.sup.+).
EXAMPLE XXI
##STR46##
Rac-trans-2-{2-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]cyclooctyloxymethyl}-6
-methylbenzoic Acid 37
trans-1,2-Cyclooctanediol, iodide 2 and bromide 4 gave the desired
product 37 of molecular weight 467.54 (C.sub.27 H.sub.30
FNO.sub.5); MS(ESI): 468 (M+H.sup.+).
EXAMPLE XXII
##STR47##
Rac-cis-2-{2-[2-(4-Fluorophenyl)oxazol4-ylmethoxy]methylcyclohexyl-methoxym
ethyl}-6-methylbenzoic Acid 38
cis-(2-Hydroxymethylcyclohexyl)methanol, iodide 2 and bromide 4
gave the product 38 of molecular weight 467.54 (C.sub.27 H.sub.30
FNO.sub.5); MS(ESI): 468 (M+H.sup.+).
EXAMPLE XXIII
##STR48##
2-{2-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]methylcyclohexylmethoxymethyl}-6
-methylbenzoic Acid 39
(3-Hydroxymethylcyclohexyl)methanol, iodide 2 and bromide 4 gave
the product 39 of molecular weight 467.54 (C.sub.27 H.sub.30
FNO.sub.5); MS(ESI): 468 (M+H.sup.+).
EXAMPLE XXIV
##STR49##
Rac-cis-2-{3-[2-(4-Fluorophenyl)oxazol-4-ylmethoxymethyl]cyclohexyloxymethy
l}-6-methylbenzoic Acid 40
cis-3-Hydroxymethylcyclohexanol, iodide 2 and bromide 4 gave
product 40 of molecular weight 453.52 (C.sub.26 H.sub.28
FNO.sub.5); MS(ESI):+454 (M+H.sup.+).
EXAMPLE XXV
##STR50##
Rac-cis-2-{3-[2-(4-Fluorophenyl)oxazol4-ylmethoxy]cyclohexylmethoxymethyl}-
6-methylbenzoic Acid 41
Reacting cis-3-hydroxymethylcyclohexanol, bromide 4 and iodide 2 in
a reverse order relative to Example XXIV gave the product 41 of
molecular weight 453.52 (C.sub.26 H.sub.28 FNO.sub.5); MS(ESI): 454
(M+H.sup.+).
EXAMPLE XXVI
##STR51##
Rac-cis-2-{3-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]cyclohexylmethoxy}-6-met
hylbenzoic Acid 42
cis-3-Hydroxymethylcyclohexanol, iodide 2 and ethyl
2-hydroxy-6-methylbenzoate gave the product 42 of molecular weight
439.49 (C.sub.25 H.sub.26 FNO.sub.5); MS(ESI): 440 (M+H.sup.+).
EXAMPLE XXVII
##STR52##
Rac-trans-2-{4-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]cyclohexylmethoxy}-6-m
ethylbenzoic Acid 43
trans-4-Hydroxymethylcyclohexanol, iodide 2 and ethyl
2-hydroxy-6-methylbenzoate gave the product 43 of molecular weight
439.49 (C.sub.25 H.sub.26 FNO.sub.5); MS(ESI): 440 (M+H.sup.+).
EXAMPLE XXVIII
##STR53##
Rac-cis-2-(2-{3-[2-(4-Fluorophenyl)oxazol-4-ylmethoxy]cyclohexyl}ethyl)-6-m
ethylbenzoic Acid 44
cis-3-Ethynylcyclohex-2-enol, ethyl
2-methyl-6-trifluoromethanesulfonyloxybenzoate and iodide 2 gave
the product 44 of molecular weight 437.52 (C.sub.26 H.sub.28
FNO.sub.4); MS(ESI): 438 (M+H.sup.+).
EXAMPLE XXIX
##STR54##
Rac-trans-2-(2-{3-[2-(4-Fluorophenyl)oxazol4-ylmethoxy]cyclohexyl}ethyl)-6-
methylbenzoic Acid 45
trans-3-Ethynylcyclohex-2-enol, ethyl
2-methyl-6-trifluoromethanesulfonyloxybenzoate and iodide 2 gave
the product 45 of molecular weight 437.52 (C.sub.26 H.sub.28
FNO.sub.4);.MS(ESI): 438 (M+H.sup.+).
EXAMPLE XXX
##STR55##
Rac-trans-2-(3-(2-(4-Fluorophenyl)oxazol4-ylmethoxy)cyclohexyloxymethyl)-6-
methylbenzoic Acid 46
The racemic trans-enantiomer mixture 3b (see Example I) and methyl
2-bromomethyl-6-methylbenzoate 4 gave the desired product 46 of
molecular weight 439.49 (C.sub.25 H.sub.26 FNO.sub.5); MS(ESI): 440
(M+H.sup.+).
EXAMPLE XXXI
##STR56##
Methyl 2-(cis-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate 47 and
methyl 2-(trans-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate
48
##STR57##
8.7 g 1,3-cyclohexanediol and 12 g dibutyltin oxide were dissolved
in 600 ml of toluene and, under reflux on a water separator, heated
to boiling. During the reaction, the reaction volume was reduced to
half of the original volume. After 4 hours, the reaction mixture
was cooled to room temperature, and 300 ml of DMF, 9.0 g of methyl
2-bromomethyl-6-methylbenzoate and 9.4 g of cesium fluoride were
added. The mixture was stirred at room temperature for 12 hours.
The reaction mixture was diluted by addition of ethyl acetate and
washed with saturated NaCl solution. The organic phase was dried
over magnesium sulfate, the solvent was removed under reduced
pressure and the residue was purified by flash chromatography on
silica gel (n-heptane/ethyl acetate=50:1.fwdarw.1:2). This gave
about 6 g of the alcohol 47 (cis-racemate) as an oil. C.sub.16
H.sub.22 O.sub.4 (278.35), MS(ESI): 279 (M+H.sup.+). The unreacted
trans-1,3-cyclohexanediol also eluted from the chromatography
column. It was alkylated analogously to Example I using sodium
hydride and methyl 2-bromomethyl-6-methylbenzoate. After analogous
work-up and chromatography as described for the cis-racemate, the
trans-racemate 48 was obtained C.sub.16 H.sub.22 O.sub.4 (278.35),
MS(ESI): 279 (M+H.sup.+).
Racemates 47 and 48 were separated by chromatography on a chiral
phase (Chiralpak AD/2 250.times.4.6;
n-heptane:ethanol:methanol=25:1:0.5+0.1 % trifluoroacetic acid,
R.sub.t (47a)=8.9 min; retention time of the enantiomer: R.sub.t
(47b)=9.9 min (the absolute retention times varied with the exact
chromatography conditions)).
The reactions described below can be carried out both with the pure
stereoisomers and with mixtures of the stereoisomers.
Methyl
2-{3-[2-(4-bromophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-
methylbenzoate 49 ##STR58##
At room temperature, 50 mg of a 60% sodium hydride suspension and
then 408 mg of 2-(4-bromophenyl)4-iodomethyl-5-methyloxazole were
added to a solution of 200 mg of methyl
2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate in 5 ml of
dimethylformamide. After one hour, methyl tert-butyl ether was
added, and the mixture was extracted with water. The organic phase
was dried over magnesium sulfate, the solvents were removed under
reduced pressure and the residue was purified by RP-HPLC. This gave
49 as a light-yellow oil. C.sub.27 H.sub.30 BrNO.sub.5 (528.45),
MS(ESI): 528.2, 530.2 (M+H.sup.+).
2-{3-[2-(4-Bromophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-m
ethylbenzoic Acid 50
##STR59##
117 mg of 49 were stirred in a mixture of 10 ml of tert-butanol and
1 ml of 10 N aqueous potassium hydroxide solution at 90.degree. C.
After two days, the mixture was acidified with hydrochloric acid
and extracted with ethyl acetate. The combined organic phases were
dried over magnesium sulfate, the solvents were removed under
reduced pressure and the residue was purified by RP-HPLC. This gave
50 as an amorphous solid. C.sub.26 H.sub.28 BrNO.sub.5 (514.52),
MS(ESI): 514.29, 516.29 (M+H.sup.+).
EXAMPLE XXXII
##STR60##
2-{3-[2-(3-Bromophenyl
)-5-methyloxazol-4-ylmethoxyjcyclohexyloxymethyl}-6-methylbenzoic
Acid 51
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(3-bromophenyl)-4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, gave the product 51 of
molecular weight 514.42, (C.sub.26 H.sub.28 BrNO.sub.5), MS(ESI):
514.30, 516.30 (M+H.sup.+).
EXAMPLE XXXIII
##STR61##
2-{3-[2-(3-Fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-
methylbenzoic Acid 52
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(3-fluorophenyl)-4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, gave the product 52 of
molecular weight 453.52 (C.sub.26 H.sub.28 FNO.sub.5), MS(ESI):
454.35 (M+H.sup.+).
EXAMPLE XXXIV
##STR62##
2-{3-[2-(3-Methoxyphenyl)-5-methyloxazol4-ylmethoxy]cyclohexyloxymethyl}-6-
methylbenzoic Acid 53
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(3-methoxyphenyl)4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, gave the product 53 of
molecular weight 465.55 (C.sub.27 H.sub.31 NO.sub.6), MS(ESI):
466.37 (M+H.sup.+).
EXAMPLE XXXV
##STR63##
2-{3-[2-(3-Trifluoromethylphenyl)-5-methyloxazol4-ylmethoxy]cyclohexyloxyme
thyl}-6-methylbenzoic Acid 54
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(3-trifluoromethylphenyl)4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, gave the product 54 of
molecular weight 503.52 (C.sub.27 H.sub.28 F.sub.3 NO.sub.5),
MS(ESI): 504.37 (M+H.sup.+).
EXAMPLE XXXVI
##STR64##
2-{3-[2-(3-Chlorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexyloxymethyl}-6-m
ethylbenzoic Acid 57
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(3-chlorophenyl)4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, gave the product 57 of
molecular weight 469.97 (C.sub.26 H.sub.28 CINO.sub.5), MS(ESI):
470.43 (M+H.sup.+).
EXAMPLE XXXVII
##STR65##
2-{3-[2-(4-Chlorophenyl)-5-methyloxazol-4-yl
methoxy]cyclohexyloxymethyl}-6-methylbenzoic Acid 58
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(4-chlorophenyl)4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, the product 58 of
molecular weight 469.97 (C.sub.26 H.sub.28 CINO.sub.5), MS(ESI):
470.40 (M+H.sup.+).
EXAMPLE XXXVIII
##STR66##
2-{3-[2-(3-Methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-
methylbenzoic Acid 59
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(3-methylphenyl)-4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, gave the product 59 of
molecular weight 449.55 (C.sub.27 H.sub.31 NO.sub.5), MS(ESI):
450.53 (M+H.sup.+).
EXAMPLE XXXIX
##STR67##
2-{3-[2-(3,4-Dimethylphenyl)-5-methyloxazol4-ylmethoxy]cyclohexyloxymethyl}
-6-methylbenzoic Acid 61
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(3,4-dimethylphenyl)-4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, gave the product 61 of
molecular weight 463.58 (C.sub.28 H.sub.33 NO.sub.5), MS(ESI):
464.22 (M+H.sup.+).
EXAMPLE XL
##STR68##
2-{3-(2-(2
,4-Dimethylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-methy
lbenzoic Acid 62
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(2,4-dimethylphenyl)-4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, gave the product 62 of
molecular weight 463.58 (C.sub.28 H.sub.33 NO.sub.5), MS(ESI):
464.22 (M+H.sup.+).
EXAMPLE XLI
##STR69##
2-{3-[2-(2-Methylphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-
methylbenzoic Acid 63
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(2-methylphenyl)-4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, gave the product 63 of
molecular weight 449.55 (C.sub.27 H.sub.31 NO.sub.5), MS(ESI):
450.20 (M+H.sup.+).
EXAMPLE XLII
##STR70##
2-{3-[2-(3-Trifluoromethoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy
methyl}-6-methylbenzoic Acid 64
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(3-trifluoromethoxyphenyl)-4-iodomethyl-5-methyloxazole as
starting materials in the procedure of Example XXXI, gave the
product 64 of molecular weight 519.52 (C.sub.27 H.sub.28 F.sub.3
NO.sub.6), MS(ESI): 520.20 (M+H.sup.+).
EXAMPLE XLIII
##STR71##
2-{3-[2-(3,4-Dimethoxyphenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethy
l}-6-methylbenzoic Acid 67
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(3,4-dimethoxyphenyl)4-iodomethyl-5-methyloxazol as starting
materials in the procedure of Example XXXI, gave the product 67 of
molecular weight 495.58 (C.sub.28 H.sub.33 NO7), MS(ESI): 496.20
(M+H.sup.+).
EXAMPLE XLIV
##STR72##
2-{3-[2-(3-Cyanophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-m
ethylbenzoic Acid 68
##STR73##
13 mg of
2-{3-[2-(3-bromophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-
methylbenzoic acid and 25 mg of zinc cyanide were dissolved in 5 ml
of dimethylformamide. The reaction mixture was degassed and charged
with argon, and 20 mg of tetrakistriphenylphosphinepalladium were
added. The mixture was stirred at 100.degree. C. for 12 hours.
After cooling to room temperature, water was added to the reaction
mixture, which was then extracted with ethyl acetate. The combined
organic phases were dried over magnesium sulfate, the solvents were
removed under reduced pressure and the residue was purified by
RP-HPLC. This gave 68 as an amorphous light-yellow solid. C.sub.27
H.sub.28 N.sub.2 O.sub.5 (460.53), MS(ESI): 461.20 (M+H.sup.+).
EXAMPLE XLV
##STR74##
2-Methyl-6-[3-(5-methyl-2-phenyloxazol-4-ylmethoxy)cyclohexyloxymethyl]benz
oic Acid 69
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-phenyl-4-iodomethyl-5-methyloxazole as starting materials in the
procedure of Example XXXI, gave the product 69 of molecular weight
435.52 (C.sub.26 H.sub.29 NO.sub.5), MS(ESI): 436.32
(M+H.sup.+).
EXAMPLE XLVI
##STR75##
2-Methyl-6-[3-(5-methyl-2-p-tolyloxazol-4-ylmethoxyscyclohexyloxyme
thyl]benzoic Acid 70
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(4-methylphenyl)-4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, gave the product 70 of
molecular weight 449.55 (C.sub.27 H.sub.31 NO.sub.5), MS(ESI):
450.36 (M+H.sup.+).
EXAMPLE XLVII
##STR76##
2-{3-[2-(4-Methoxyphenyl
)-5-methyloxazol4-ylmethoxy]cyclohexyloxymethyl}-6-methylbenzoic
Acid 71
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and
2-(4-methoxyphenyl)-4-iodomethyl-5-methyloxazole as starting
materials in the procedure of Example XXXI, gave the product 71 of
molecular weight 465.55 (C.sub.27 H.sub.31 NO.sub.6), MS(ESI):
466.37 (M+H.sup.+).
While the invention has been described in connection with certain
preferred embodiments so that aspects thereof may be more fully
understood and appreciated, it is not intended to limit the
invention to these particular embodiments. On the contrary, it is
intended to cover all alternatives, modifications and equivalents
as may be included within the scope of the invention as defined by
the appended claims.
* * * * *
References